tbuckley/cabot-search huggingface dataset:
Air Pollution and Pediatric Respiratory Hospitalizations: Effect Modification by Particle Constituents and Oxidative Potential
Authors: Jill Korsiak, Eric Lavigne, Hongyu You, Krystal Pollitt, Ryan Kulka, Marianne Hatzopoulou, Greg Evans, Richard T. Burnett, Scott Weichenthal
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Outdoor particulate and gaseous air pollutants impair respiratory health in children, and these associations may be influenced by particle composition. Objectives: To examine whether associations between short-term variations in fine particulate air pollution, oxidant gases, and respiratory hospitalizations in children are modified by particle constituents (metals and sulfur) or oxidative potential. Methods: We conducted a case-crossover study of 10,500 children (0–17 years of age) across Canada. Daily fine particle mass concentrations and oxidant gases (nitrogen dioxide and ozone) were collected from ground monitors. Monthly estimates of fine particle constituents (metals and sulfur) and oxidative potential were also measured. Conditional logistic regression models were used to estimate associations between air pollutants and respiratory hospitalizations, above and below median values for particle constituents and oxidative potential. Measurements and Main Results: Lag-1 fine particulate matter mass concentrations were not associated with respiratory hospitalizations (odds ratio and 95% confidence interval per 10 μg/m3 increase in fine particulate matter: 1.004 [0.955–1.056]) in analyses ignoring particle constituents and oxidative potential. However, when models were examined above or below median metals, sulfur, and oxidative potential, positive associations were observed above the median. For example, the odds ratio and 95% confidence interval per 10 μg/m3 increase in fine particulate matter were 1.084 (1.007–1.167) when copper was above the median and 0.970 (0.929–1.014) when copper was below the median. Similar trends were observed for oxidant gases. Conclusions: Stronger associations were observed between outdoor fine particles, oxidant gases, and respiratory hospitalizations in children when metals, sulfur, and particle oxidative potential were elevated.
Next-generation ALK inhibitors are highly active in ALK-positive large B-cell lymphoma
Authors: Jacob D. Soumerai, Allison Rosenthal, Shannon Harkins, Jessica Duffy, Carmen Mecca, Yingbing Wang, Ravinder K. Grewal, Areej R. El-Jawahri, Huiyun Liu, Cedric Menard, Ahmet Dogan, Lei Yang, Lisa M. Rimsza, Kurt Bantilan, Haley Martin, Matthew Lei, Sydney Mohr, Anna Kurilovich, Olga Kudryashova, Ekaterina Postovalova, Valentina Nardi, Jeremy S. Abramson, Roberto Chiarle, Andrew D. Zelenetz, Abner Louissaint
Journal: Blood (2022)

Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma is a rare large B-cell lymphoma subtype that is characterized by a plasmablastic phenotype and an ALK gene fusion. ALK-positive large B-cell lymphoma is resistant to the first-generation ALK inhibitor crizotinib and uniformly fatal with few if any complete responses in the relapsed setting, where no long-term survivors have been reported in the literature. No standard therapies exist for patients with relapsed or refractory disease, and its rarity and lethality have precluded prospective clinical research. Herein, we report the generation of the first ALK-positive large B-cell lymphoma patient-derived xenograft model, in which we show that next-generation ALK inhibitors are therapeutically active. On this basis, we administered the next-generation ALK inhibitor alectinib to four consecutive patients (three crizotinib-refractory). All four responded (two complete responses), one in ongoing remission after allogeneic transplantation &amp;gt;15 months. One with progressive disease was treated with lorlatinib and achieved complete response. These data support use of alectinib and lorlatinib as off-label therapeutic options for patients with relapsed or refractory ALK-positive large B-cell lymphoma.
Quantitative proteomic landscapes of primary and recurrent glioblastoma reveal a protumorigeneic role for FBXO2-dependent glioma-microenvironment interactions
Authors: Marcel Buehler, Xiao Yi, Weigang Ge, Peter Blattmann, Elisabeth Rushing, Guido Reifenberger, Joerg Felsberg, Charles Yeh, Jacob E Corn, Luca Regli, Junyi Zhang, Ann Cloos, Vidhya M Ravi, Benedikt Wiestler, Dieter Henrik Heiland, Ruedi Aebersold, Michael Weller, Tiannan Guo, Tobias Weiss
Journal: Neuro-Oncology (2022)

Abstract Background Recent efforts have described the evolution of glioblastoma from initial diagnosis to post-treatment recurrence on a genomic and transcriptomic level. However, the evolution of the proteomic landscape is largely unknown. Methods Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was used to characterize the quantitative proteomes of two independent cohorts of paired newly diagnosed and recurrent glioblastomas. Recurrence-associated proteins were validated using immunohistochemistry and further studied in human glioma cell lines, orthotopic xenograft models, and human organotypic brain slice cultures. External spatial transcriptomic, single-cell, and bulk RNA sequencing data were analyzed to gain mechanistic insights. Results Although overall proteomic changes were heterogeneous across patients, we identified BCAS1, INF2, and FBXO2 as consistently upregulated proteins at recurrence and validated these using immunohistochemistry. Knockout of FBXO2 in human glioma cells conferred a strong survival benefit in orthotopic xenograft mouse models and reduced invasive growth in organotypic brain slice cultures. In glioblastoma patient samples, FBXO2 expression was enriched in the tumor infiltration zone and FBXO2-positive cancer cells were associated with synaptic signaling processes. Conclusions These findings demonstrate a potential role of FBXO2-dependent glioma-microenvironment interactions to promote tumor growth. Furthermore, the published datasets provide a valuable resource for further studies.
NF-κB signaling controls H3K9me3 levels at intronic LINE-1 and hematopoietic stem cell genes in cis
Authors: Yanis Pelinski, Donia Hidaoui, Anne Stolz, François Hermetet, Rabie Chelbi, M’boyba Khadija Diop, Amir M. Chioukh, Françoise Porteu, Emilie Elvira-Matelot
Journal: The Journal of Experimental Medicine (2022)

Ionizing radiations (IR) alter hematopoietic stem cell (HSC) function on the long term, but the mechanisms underlying these effects are still poorly understood. We recently showed that IR induces the derepression of L1Md, the mouse young subfamilies of LINE-1/L1 retroelements. L1 contributes to gene regulatory networks. However, how L1Md are derepressed and impact HSC gene expression are not known. Here, we show that IR triggers genome-wide H3K9me3 decrease that occurs mainly at L1Md. Loss of H3K9me3 at intronic L1Md harboring NF-κB binding sites motifs but not at promoters is associated with the repression of HSC-specific genes. This is correlated with reduced NFKB1 repressor expression. TNF-α treatment rescued all these effects and prevented IR-induced HSC loss of function in vivo. This TNF-α/NF-κB/H3K9me3/L1Md axis might be important to maintain HSCs while allowing expression of immune genes during myeloid regeneration or damage-induced bone marrow ablation.
Broadening prime editing toolkits using RNA-Pol-II-driven engineered pegRNA
Authors: Shisheng Huang, Zhenwu Zhang, Wanyu Tao, Yao Liu, Xiangyang Li, Xiaolong Wang, Javad Harati, Peng-Yuan Wang, Xingxu Huang, Chao-Po Lin
Journal: Molecular Therapy (2022)

The prime editor is a versatile tool for targeted precise editing to generate point mutations, small insertions, or small deletions in eukaryotes. However, canonical PE3 system is less efficient, notably in primary cells or pluripotent stem cells. Here, we employed RNA polymerase II promoter instead of RNA polymerase III promoter, whose application is limited by specific DNA contexts, to produce Csy4-processed intronic prime editing guide RNAs (pegRNAs) and, together with other optimizations, achieved efficient targeting with poly(T)-containing pegRNAs, as well as combinatorial and conditional genetic editing. We also found simultaneous suppression of both DNA mismatch repair and DNA damage response could achieve efficient and accurate editing in human embryonic stem cells. These findings relieve the restrictions of RNA polymerase III (RNA-Pol-III)-based base editors and broadened the applications of prime editing.
Novel retinal vascular phenotypes for the potential assessment of long-term risk in living kidney donors
Authors: Ylenia Giarratano, Dan Pugh, Tariq E. Farrah, Gabriel C. Oniscu, Thomas J. MacGillivray, Baljean Dhillon, Neeraj Dhaun, Miguel O. Bernabeu
Journal: Kidney International (2022)

Chronic kidney disease (CKD) has a global prevalence of ≈10% and is independently associated with incident cardiovascular disease (CVD).1 The risk of CVD increases as estimated glomerular filtration rate (eGFR) declines and is highest in those with kidney failure.1 Kidney transplantation prolongs survival of patients with kidney failure, and transplantation of a kidney from a living donor is considered the optimal form of renal replacement therapy. However, kidney donation may be associated with longer-term risks of developing both CKD and CVD.
Association Between Residence in Historically Redlined Districts Indicative of Structural Racism and Racial and Ethnic Disparities in Breast Cancer Outcomes
Authors: Jesse J. Plascak, Kirsten Beyer, Xinyi Xu, Antoinette M. Stroup, Gabrielle Jacob, Adana A. M. Llanos
Journal: JAMA Network Open (2022)

Historical structural racism may be associated with racial, ethnic, and geographic disparities in breast cancer outcomes, but few studies have investigated these potential relationships.To test associations among historical mortgage lending discrimination (using 1930s Home Owners' Loan Corporation [HOLC] redlining data), race and ethnicity, tumor clinicopathologic features, and survival among women recently diagnosed with breast cancer.This cohort study used a population-based, state cancer registry to analyze breast tumor clinicopathology and breast cancer-specific death among women diagnosed from 2008 to 2017 and followed up through 2019. Participants included all primary, histologically confirmed, invasive breast cancer cases diagnosed among women aged at least 20 years and who resided in a HOLC-graded area of New Jersey. Those missing race and ethnicity data (n = 61) were excluded. Data were analyzed between June and December 2021.HOLC risk grades of A ("best"), B ("still desirable"), C ("definitely declining"), and D ("hazardous" [ie, redlined area]).Late stage at diagnosis, high tumor grade, triple-negative subtype (lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression), breast cancer-specific death.Among a total of 14 964 women with breast cancer, 2689 were Latina, 3506 were non-Latina Black, 7686 were non-Latina White, and 1083 were other races and ethnicities (non-Latina Asian/Pacific Islander/Native American/Alaska Native/Hawaiian or not otherwise specified); there were 1755 breast cancer-specific deaths. Median follow-up time was 5.3 years (95% CI, 5.2-5.3 years) and estimated 5-year breast cancer-specific survival was 88.0% (95% CI, 87.4%-88.6%). Estimated associations between HOLC grade and each breast cancer outcome varied by race and ethnicity; compared with residence in HOLC redlined areas, residence in HOLC areas graded "best" was associated with lower odds of late-stage diagnosis (odds ratio [OR], 0.34 [95% CI, 0.22-0.53]), lower odds of high tumor grade (OR, 0.72 [95% CI, 0.57-0.91]), lower odds of triple-negative subtype (OR, 0.67 [95% CI, 0.47-0.95]), and lower hazard of breast cancer-specific death (hazard ratio, 0.48 [95% CI, 0.35-0.65]), but only among non-Latina White women. There was no evidence supporting associations among non-Latina Black or Latina women.Compared with redlined areas, current residence in non-redlined areas was associated with more favorable breast cancer outcomes, but only among non-Latina White women. Future studies should examine additional factors to inform how historical structural racism could be associated with beneficial cancer outcomes among privileged racial and ethnic groups.
Machine learning models are superior to noninvasive tests in identifying clinically significant stages of NAFLD and NAFLD‐related cirrhosis
Authors: Devon Chang, Emily Truong, Edward A. Mena, Fabiana Pacheco, Micaela Wong, Maha Guindi, Tsuyoshi T. Todo, Nabil Noureddin, Walid Ayoub, Ju Dong Yang, Irene K. Kim, Anita Kohli, Naim Alkhouri, Stephen Harrison, Mazen Noureddin
Journal: Hepatology (2022)

We assessed the performance of machine learning (ML) models in identifying clinically significant NAFLD-associated liver fibrosis and cirrhosis.We implemented ML models including logistic regression (LR), random forest (RF), and artificial neural network to predict histological stages of fibrosis using 17 demographic/clinical features in 1370 patients with NAFLD who underwent liver biopsy, FibroScan, and labs within a 6-month period at multiple U.S. centers. Histological stages of fibrosis (≥F2, ≥F3, and F4) were predicted using ML, FibroScan liver stiffness measurements, and Fibrosis-4 index (FIB-4). NASH with significant fibrosis (NAS ≥ 4 + ≥F2) was assessed using ML, FibroScan-AST (FAST) score, FIB-4, and NAFLD fibrosis score (NFS). We used 80% of the cohort to train and 20% to test the ML models. For ≥F2, ≥F3, F4, and NASH + NAS ≥ 4 + ≥F2, all ML models, especially RF, had primarily higher accuracy and AUC compared with FibroScan, FIB-4, FAST, and NFS. AUC for RF versus FibroScan and FIB-4 for ≥F2, ≥F3, and F4 were (0.86 vs. 0.81, 0.78), (0.89 vs. 0.83, 0.82), and (0.89 vs. 0.86, 0.85), respectively. AUC for RF versus FAST, FIB-4, and NFS for NASH + NAS ≥ 4 + ≥F2 were (0.80 vs. 0.77, 0.66, 0.63). For NASH + NAS ≥ 4 + ≥F2, all ML models had lower/similar percentages within the indeterminate zone compared with FIB-4 and NFS. Overall, ML models performed better in sensitivity, specificity, positive predictive value, and negative predictive value compared with traditional noninvasive tests.ML models performed better overall than FibroScan, FIB-4, FAST, and NFS. ML could be an effective tool for identifying clinically significant liver fibrosis and cirrhosis in patients with NAFLD.
Bidirectional roles of skeletal muscle fibro-adipogenic progenitors in homeostasis and disease
Authors: Wentao Chen, Wenjing You, Teresa G. Valencak, Tizhong Shan
Journal: Ageing Research Reviews (2022)

Sarcopenia and myopathies cause progressive muscle weakness and degeneration, which are closely associated with fat infiltration and fibrosis in muscle. Recently, experimental research has shed light on fibro-adipogenic progenitors (FAPs), also known as muscle-resident mesenchymal progenitors with multiple differentiation potential for adipogenesis, fibrosis, osteogenesis and chondrogenesis. They are considered key regulators of muscle homeostasis and integrity. They play supportive roles in muscle development and repair by orchestrating the regulatory interplay between muscle stem cells (MuSCs) and immune cells. Interestingly, FAPs also contribute to intramuscular fat infiltration, fibrosis and other pathologies when the functional integrity of the network is compromised. In this review, we summarize recent insights into the roles of FAPs in maintenance of skeletal muscle homeostasis, and discuss the underlying mechanisms regulating FAPs behavior and fate, highlighting their roles in participating in efficient muscle repair and fat infiltrated muscle degeneration as well as during muscle atrophy. We suggest that controlling and predicting FAPs differentiation may become a promising strategy to improve muscle function and prevent irreparable muscle damage.
Arthroscopic Treatment of Degenerative Meniscal Tears and Sham Surgery or Physical Therapy—an Update on the ESCAPE Trial
Authors: Brian Hallstrom, Ramzy Meremikwu
Journal: JAMA Network Open (2022)

Julia C. A. Noorduyn, MSc; Victor A. van de Graaf, MD, PhD; Nienke W. Willigenburg, PhD; Gwendolyne G. M. Scholten-Peeters, PhD; Esther J. Kret, MSc; Rogier A. van Dijk, MD, PhD; Rachelle Buchbinder, MD, PhD; Gillian A. Hawker, MD, PhD; Michel W. Coppieters, PhD; Rudolf W. Poolman, MD, PhD; ESCAPE Research Group
Autologous T cell responses to primary human colorectal cancer spheroids are enhanced by ectonucleotidase inhibition
Authors: Julie Bonnereau, Tristan Courau, Nicolas Asesio, Delphine Salfati, Fatiha Bouhidel, Hélène Corte, Sarah Hamoudi, Nassim Hammoudi, Julie Lavolé, Justine Vivier-Chicoteau, Victor Chardiny, Leon Maggiori, Mathieu Blery, Romain Remark, Cécile Bonnafous, Pierre Cattan, Antoine Toubert, Purnima Bhat, Matthieu Allez, Thomas Aparicio, Lionel Le Bourhis
Journal: Gut (2022)

Objective T cells are major effectors of the antitumoural immune response. Their activation by tumour-associated antigens can unleash their proliferation and cytotoxic functions, leading to tumour cell elimination. However, tumour-related immunosuppressive mechanisms including the overexpression of immune checkpoints like programmed cell death protein-1 (PD-1), are also engaged, promoting immune escape. Current immunotherapies targeting these pathways have demonstrated weak efficacy in colorectal cancer (CRC). It is thus crucial to find new targets for immunotherapy in this cancer type. Design In a prospective cohort of patients with CRC, we investigated the phenotype of tumour-related and non-tumour related intestinal T cells (n=44), particularly the adenosinergic pathway, correlating with clinical phenotype. An autologous coculture model was developed between patient-derived primary tumour spheroids and their autologous tumour-associated lymphocytes. We used this relevant model to assess the effects of CD39 blockade on the antitumour T cell response. Results We show the increased expression of CD39, and its co-expression with PD-1, on tumour infiltrating T cells compared with mucosal lymphocytes. CD39 expression was higher in the right colon and early-stage tumours, thus defining a subset of patients potentially responsive to CD39 blockade. Finally, we demonstrate in autologous conditions that CD39 blockade triggers T cell infiltration and tumour spheroid destruction in cocultures. Conclusion In CRC, CD39 is strongly expressed on tumour infiltrating lymphocytes and its inhibition represents a promising therapeutic strategy for treating patients.
Discriminatory Changes in Circulating Metabolites as a Predictor of Hepatocellular Cancer in Patients with Metabolic (Dysfunction) Associated Fatty Liver Disease
Authors: Haonan Lu, Jacob George, Mohammed Eslam, Augusto Villanueva, Luigi Bolondi, Helen L. Reeves, Misti McCain, Edward Chambers, Caroline Ward, Dewi Sartika, Caroline Sands, Lynn Maslen, Matthew R. Lewis, Ramya Ramaswami, Rohini Sharma
Journal: Liver Cancer (2022)

Introduction: The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterized by perturbations in lipid handling, inflammation, and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC. Methods: We assessed the profile of 273 lipid and small molecule metabolites by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry in serum from patients with MAFLD (n = 113) and MAFLD-associated HCC (n = 144) from six different centers. Regression models were used to identify a predictive model of HCC. Results: Twenty lipid species and one metabolite, reflecting changes in mitochondrial function and sphingolipid metabolism, were associated with the presence of cancer on a background of MAFLD with high accuracy (AUC 0.789, 95% CI: 0.721–0.858), which was enhanced with the addition of cirrhosis to the model (AUC 0.855, 95% CI: 0.793–0.917). In particular, the presence of these metabolites was associated with cirrhosis in the MAFLD subgroup (p &lt; 0.001). When considering the HCC cohort alone, the metabolic signature was an independent predictor of overall survival (HR 1.42, 95% CI: 1.09–1.83, p &lt; 0.01). Conclusion: These exploratory findings reveal a metabolic signature in serum which is capable of accurately detecting the presence of HCC on a background of MAFLD. This unique serum signature will be taken forward for further investigation of diagnostic performance as biomarker of early stage HCC in patients with MAFLD in the future.
Anti-GD2 Antibodies Conjugated to IL15 and IL21 Mediate Potent Antitumor Cytotoxicity against Neuroblastoma
Authors: Rosa Nguyen, Xiyuan Zhang, Ming Sun, Shahroze Abbas, Charlie Seibert, Michael C. Kelly, Jack F. Shern, Carol J. Thiele
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Half of the patients with high-risk neuroblastoma who receive GD2-targeted mAb do not achieve long-term remissions. Recently, the antibody hu14.18 has been linked to IL2 (hu14.18-IL2) to enhance its efficacy and shown promising preclinical and clinical activity. We developed two new immunocytokines (IC) by linking two other γc cytokines, IL15 and IL21, to hu14.18. The purpose of this study was to compare hu14.18-IL15 and -IL21 with hu14.18-IL2 in their ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) against neuroblastoma. Experimental Design: We assessed ADCC of hu14.18-IL15 and -IL2 (human cytokines, cross-reactive to mouse) against GD2low and GD2high neuroblastoma cell lines in vitro. T-cell–deficient mice with orthotopic patient-derived xenografts (PDX) and immunocompetent mice with transplantable orthotopic neuroblastoma were used to test all three ICs, including hu14.18-IL21 (murine IL21, not cross-reactive to human). Mechanistic studies were performed using single-cell RNA-sequencing (scRNA-seq). Results: hu14.18-IL15 and hu14.18-IL2 mediated equivalent in vitro ADCC by human NK cells. When combined with chemotherapy, all three ICs similarly controlled the growth of PDXs in nude mice with murine NK effector cells. However, hu14.18-IL15 and -IL21 outperformed hu14.18-IL2 in immunocompetent mice with syngeneic neuroblastoma, inducing complete tumor regressions and extending survival. scRNA-seq data revealed an increase in CD8+ T cells and M1 tumor-associated macrophages and decreased regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment. Conclusions: Hu14.18-IL15 and Hu14.18-IL21 exhibit robust preclinical activity, warranting further consideration for clinical testing in patients with GD2-expressing neuroblastoma.